The basic genetic defect responsible for cystic fibrosis (CF) is as yet unknown, and its elaboration should ultimately result in improving the treatment of this disease. There have been reports that alpha macroglobulin (alpha 2M) from plasma, which is known to inhibit protease activity, is less potent as an inhibitor in CF patients. This difference suggests a structural variation that might be the result of a genetic defect. These reports have, however, been controversial, and the work thus far in this laboratory has centered on confirming and extending the reports on alpha 2M. This protein may be digested with trypsin. Early indications have suggested a difference in the rate of digestion, that of the CF alpha 2M being slower.